Could you briefly introduce the Southern Hemisphere Influenza and Vaccine Effectiveness Research & Surveillance (SHIVERS) project?

The SHIVERS project is the result of a successful application to a Funding Opportunity Announcement from the US Centers for Disease Control and Prevention (CDC) to evaluate influenza and other respiratory diseases in the Southern Hemisphere. The project is a multi-agency collaboration and is designed to understand the impact of influenza nationally and globally. Overall, SHIVERS aims to evaluate influenza disease burden, epidemiology, aetiology, risk factors and immunology, along with the effectiveness of prevention strategies such as vaccination for influenza and other respiratory diseases of public health importance.

With this in mind, we have developed two active, population-based surveillance platforms covering a cohort of 838,000 residents living in New Zealand. We are employing hospital-based surveillance for hospitalised severe acute respiratory illness (SARI) and associated infections, as well as sentinel general practice-based surveillance for consultation-seeking influenza-like illness (ILI) and associated influenza and other respiratory infections. Innovative epidemiological methods will be used to measure vaccine effectiveness in the general population and subgroup; novel methods will be utilised to assess influenza-specific humoral and cellular immune responses in individuals with varying disease severity; and new molecular strategies will be employed to assist the timely identification of known and unknown aetiologic organisms that cause respiratory disease.

Why were the different SHIVERS partners selected to contribute?

The SHIVERS research team – which comprises the Institute of Environmental Science and Research, Auckland District Health Board, Counties Manukau District Health Board, University of Auckland and University of Otago in New Zealand, as well as St Jude Children’s Research Hospital and the CDC in the US – has been carefully selected to have the skills, knowledge and experience to address the study objectives, meet the scientific and design criteria, and deliver results that will make a difference to the way influenza is managed in the future, both in New Zealand and globally. Members of the research team include clinicians, scientists and academics who have successfully collaborated on influenza-related

Through her current project, Dr Sue Huang aims to better understand influenza in the hope of curbing future outbreaks

An insight into influenza

SHIV

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INFLUENZA VIRUSES ARE a common source of illness worldwide and possess several characteristics that create severe challenges for medical systems. Commonly known as a source of fever and respiratory problems during winter months, flu can pose a serious or even fatal threat to individuals with weakened immune systems. Previous pandemics, such as the 1918 Spanish flu outbreak, have killed millions of individuals worldwide, and many scientists fear that it is only a matter of time before the next deadly variant strikes. While vaccination programmes have been successful at partially attenuating the spread of the virus, its high mutation rate and ability to mix the genetic material of different virus subtypes mean that new strains are constantly evolving.

It was exactly this trickiness, however, that first drew Dr Sue Huang of the Institute of Environmental Science and Research (ESR), New Zealand, to the virus: “I became fascinated by the influenza virus largely because of its enormous impact on the population – particularly vulnerable subgroups,” she recalls. “My dream is that one day we will be on top of it, rather than just chasing its tail!”

THE SHIVERS SOLUTION

Thanks to the Southern Hemisphere Influenza and Vaccine Effectiveness Research & Surveillance (SHIVERS) project, Huang has a unique opportunity to better understand the influenza virus. The SHIVERS project is a collaborative undertaking led by ESR in conjunction with key research and clinical partners. Funded by the US Centers for Disease Control and Prevention, SHIVERS is the largest and most comprehensive influenza research initiative in the Southern Hemisphere, and aims to build a comprehensive picture of how the flu virus spreads, mutates and interacts with other pathogens.

This is being achieved through the operation of two active, prospective, population-based surveillance platforms covering a cohort of 838,000 residents in Auckland, New Zealand. The first platform is hospital-based, monitoring incidence of hospitalisation connected with severe acute respiratory illness (SARI) and associated infections, including influenza – the first of its kind in a developed nation. The second platform is sentinel general practice-based, surveying general practice consultations relating to influenza-like illnesses (ILI), associated influenza and other respiratory infections. “Our innovative study design has multiple interconnected objectives and aims to maximise efficiency and study power,” explains Huang. Overall, the aim is to gather a library of epidemiological information relating to influenza – including demographics, presentation, comorbidity, outcome and risk factors – as well as to test the effectiveness of the influenza vaccine.

GAINING GROUND

Despite only having been in operation since 2012, SHIVERS has already made a number of significant contributions to scientific understanding and public health policy around influenza. For example, its first-year findings (2012-13) painted a picture of disease burden, indicating that 54 of every 100,000 people in New Zealand were hospitalised

One step ahead The Southern Hemisphere Influenza and Vaccine Effectiveness Research & Surveillance project is a multi-agency, interdisciplinary undertaking aiming to better understand the spread and evolution of flu and other respiratory pathogens, as well as related illnesses

research previously, so the collaboration is highly collegial and productive. The collective expertise of the group and the strength of the collaboration is a critical component to the success of the project.

As the project continues to evolve, what areas do you wish to concentrate on?

Over the forthcoming years, SHIVERS will help us to understand the full burden of disease; delineate the contributions of organism, host and environmental factors, as well as opportunities for intervention; assess the impact of co-infections; and elucidate the nature of adaptive immune responses in determining an individual’s risk of acquiring infection.

Why is New Zealand the ideal place for a population-based study of influenza? Can the results be applied to other regions of the world?

A number of factors combine to make New Zealand an excellent location for population-based research. Its predominantly publically funded healthcare system means that all New Zealanders are assigned a unique health identity number, which allows easy tracking of healthcare utilisation over time and linkage to multiple health information databases. Meanwhile, primary care providers maintain highly computerised records with detailed demographic, risk factor and immunisation status information. Furthermore, the New Zealand population is well characterised in terms of demographic structure, particularly by ethnicity and socioeconomic status.

This platform is relevant, not only for New Zealand policy, but also for the wider region and the world. SHIVERS will provide robust systematic virologic, epidemiologic and vaccine effectiveness data on circulating pandemic or seasonal influenza viruses at a time when circulation in the Northern Hemisphere is low. This could provide valuable information on all emergent respiratory pathogens that have some winter seasonality.

What impact do you predict SHIVERS will have on health at the national, regional and global scales?

Our hope is that SHIVERS will shed more light on the burden of influenza and other respiratory pathogens in this population, estimate key epidemiologic parameters for new influenza viruses with pandemic potential and other emerging viruses, and ultimately provide a framework for the timely assessment of severity which is essential in an event of emergence of these pathogens. The results derived from SHIVERS will provide extensive data to guide improved methods for disease surveillance; improve clinical case management and laboratory diagnosis; inform vaccine strain selection and vaccine development; guide targeted vaccination strategies for populations and subgroups; understand host immune responses; and identify better immune diagnostic markers.

SHIVERS is the largest and most

comprehensive influenza research

initiative in the Southern Hemisphere

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with SARI-associated influenza over the course of the year, with the very young (four-years-old or younger) and elderly (over 65) being disproportionately affected. This, when combined with the fact that just 6 per cent of young children were found to have received an influenza vaccination, prompted the New Zealand Government to adapt its public health policy to extend free influenza vaccinations to young children with significant respiratory illness (a major risk factor).

The second year’s findings (2013) have been no less fruitful, revealing ILI-associated consultation rates within general practices to be approximately 14 times greater than the corresponding SARI-associated influenza hospitalisation rate. Subgroups including school-age children, pre-schoolers, adults, those of Asian ethnicity and those with higher socioeconomic status were more likely to present for consultation with ILI, while the very young, elderly, indigenous Maori and Pacific Peoples, and those with lower socioeconomic status were more likely to require hospitalisation with SARI-associated influenza. This knowledge may provide valuable clues into how best to target prevention and treatment strategies towards specific populations.

SHIVERS has also provided an ideal opportunity to establish vaccination effectiveness in terms of prevention of general practice consultations and hospitalisations. Data from last year suggested moderate effectiveness, with vaccination providing 52 per cent protection against lab-confirmed influenza hospitalisation and 56 per cent protection against influenza presenting to general practice.

GLOBAL APPLICATIONS

SHIVERS’ benefits do not stop at New Zealand’s borders; rather, the project is already having global applications. The type of information being produced, for example, is of great use to the World Health Organization (WHO), who are tasked with preparing the international response for potential forthcoming pandemics months in advance. Since the 1970s, WHO’s Global Influenza Surveillance and Response System has provided formal recommendations on influenza vaccine composition based on year-round surveillance of changes in the characteristics and epidemiological impact of circulating viruses. Small changes to recommendations for flu vaccines in a given year can have a major impact on health spending worldwide and prevent the occurrence of thousands of new cases. “SHIVERS can contribute to this process by providing WHO with evidence of temporal and geographical spread of a variant and associated antigenic and genetic characterisation,” Huang elucidates. “We also contribute timely information of influenza vaccine effectiveness to WHO.” In addition, SHIVERS has also contributed to the finalisation of the WHO SARI case definition for global influenza surveillance.

SHIVERSSOUTHERN HEMISPHERE INFLUENZA AND VACCINE EFFECTIVENESS RESEARCH & SURVEILLANCE

KEY COLLABORATORS

Dr Don Bandaranayake; Dr Graham Mackereth; Ruth Seeds; Dr Sarah Radke; Tim Wood; Dr Ange Bissielo; Angela Todd; Dr Thomas Metz, Institute of Environmental Science and Research, New Zealand

Dr Colin McArthur; Dr Sally Roberts; Dr Cameron Grant; Dr Debbie Williamson; Debbie Aley, Auckland District Health Board, New Zealand

Dr Adrian Trenholme; Dr Conroy Wong; Dr Susan Taylor; Shirley Lawrence; Kirstin Davey, Counties Manukau District Health Board, New Zealand

Dr Nikki Turner; Barbara McArdle, University of Auckland, New Zealand

Professor Michael Baker; Dr Nevil Pierse, University of Otago, New Zealand

Dr Richard Webby; Dr Paul Thomas, St Jude Children’s Research Hospital, USA

Dr Marc-Alain Widdowson; Dr Mark Thompson; Dr Jazmin Duque; Dr Diane Gross, US Centers for Disease Control and Prevention, USA

FUNDING

US Centers for Disease Control and Prevention – grant no. 5U01IP000480

CONTACT

Dr Sue Huang Principal Investigator

Institute of Environmental Science & Research National Centre for Biosecurity & Infectious Disease 66 Ward Street Wallaceville Upper Hutt 5018 New Zealand

T +64 4 529 0606 E sue.huang@esr.cri.nz

www.esr.cri.nz/competencies/shivers

SUE HUANG is an internationally renowned virologist with a PhD from the University of Pennsylvania in Philadelphia, USA. Her area of expertise is human viruses, particularly influenza, polio and other enteroviruses that cause a range of human illnesses. She has reached pre-eminence at a national and international level through scientific leadership, publications, funding track records and reference/diagnostic services.

ONWARDS AND UPWARDS

SHIVERS is a constantly evolving project, continually adapting and improving throughout its five-year duration. For example, it has become apparent that SARI surveillance, in its current incarnation, can underestimate the full burden of influenza hospitalisations, due to factors such as atypical clinical presentations or short patient stays not being picked up. The SHIVERS team is therefore addressing this by systematically expanding case ascertainment and lab confirmation of cases.

Excitingly, there are also plans to initiate a prospective, longitudinal cohort serological study. This will provide disease burden data that take into account infections that are both asymptomatic and symptomatic, mild disease not requiring a general practice visit, and moderate, severe and fatal cases. Ultimately, these data may be used to delineate how immune responses vary between individuals.

Clearly, dealing with influenza infection and spread is a great challenge, but Huang is confident that the data collected in SHIVERS have the potential to generate epidemiologic parameters that are generally applicable both in New Zealand and across the globe. “My biggest hope is that we may support the global use of vaccines and assist in effectively preparing for the next pandemic,” she concludes.

SHIVERS’ OBJECTIVES

SHIVERS has two primary objectives:

• To understand severe acute respiratory infections

• To assess influenza vaccine effectiveness

Additionally, SHIVERS aims:

• To investigate interaction between influenza and other respiratory pathogens

• To ascertain the causes of respiratory mortality

• To understand non-severe respiratory illness

• To estimate influenza infection through a serosurvey

• To identify influenza risk factors

• To study the immune response to influenza

• To determine the healthcare and socioeconomic burden and vaccine cost-effectiveness of influenza

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